The goal of this research proposal is to identify molecular pathways involving minibrain kinase (mnbK), both in normal neuronal function and in the cognitive defects of Down syndrome. Studies of partial trisomy of chromosome 21 suggest that a considerable portion of the Down syndrome phenotype result from a 2-Mb region at the 21g22.2 region; mnbK localizes to this genomic region. Overexpression of mnbK in mice causes severe defects in learning and memory, strongly implicating mnbK in the cognitive defects of Down syndrome. Currently, the substrates and regulators of mnbK are unknown. To elucidate this pathway, the Caenorhabditis elegans mnbK homologues mbk-1 and mbk-2, will be investigated. I propose to characterize the expression and subcellular localization of the mbk gene products, generate null alleles via chemical mutagenesis coupled with population PCR, and simulate the Down condition by overexpressing the wildtype and activated gene products. As a tool for determing the focus of MBK activity, the tetracycline-dependent transactivator system will be adapted to C. elegans, a system that permits temporally and spatially regulated gene expression. Candidate genes will be tested to determine if they belong to a mbk pathway, and pilot suppressor and/or enhancer screens will be performed to identify upstream and downstream components in an unbiased manner.